One of the limiting factors in the pharmacokinetic behavior of many therapeutic drugs is drug uptake by target cells. For many small, uncharged drug compounds, drug permeation across the cell membrane may allow relatively efficient drug uptake by the cell. However, for a variety of larger and/or charged compounds, such as proteins, nucleic acids, and highly water soluble charged organic compounds, passive uptake cell by permeation across the cell membrane may be so limited as to effectively block drug uptake into the cells.
Several methods for enhancing drug uptake into cells have been proposed. In one general approach, a drug is administered in modified or prodrug form, e.g., with masked charged, for transport into cells. The drug can then be enzymatically converted to an active form within the cells.
Alternatively, the drug compound may be coupled to a carrier molecule, such as transfectin, for transport across the cell membrane. Once inside the cell, the carrier moiety may be removed enzymatically, e.g., by an intracellular esterase or protease.
Another approach to enhancing drug uptake by cells exploits the ability of many cells to engulf particles by endocytosis. Here the drug compound is entrapped in particles, typically particles with sizes less than 200-300 .mu.m, with the particles being administered for targeting to the cells of interest. Liposomes and polymer microparticles are examples of carrier particles that have been used for this purpose.
This approach is limited to certain cell types only, e.g., macrophages, which are active in particle uptake. Another limitation of the approach is that the normal course of intracellular processing involves particle uptake into lysosomes, where the therapeutic compound, e.g., a nucleic acid, can be enzymatically degraded.
Still another approach to enhancing drug uptake by cells involves the use of fusogenic particles designed to fuse with a target cell membrane, releasing the particle contents into the cell interior. Inactivated virus particles have been widely proposed for this purpose, particularly in the context of gene therapy, for introducing large nucleic acid strands into cells. Virus-like particles composed of fusion-promoting viral proteins embedded in artificial lipid bilayer membranes are another example. In both cases, safety concerns and the expense associated with growing, isolating, and deactivating viral components may limit this approach.
It would therefore be desirable to provide a drug-delivery vehicle that substantially overcomes problems associated with present methods of drug delivery to cells, as outlined above.